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MIMM 324 > 10. Papillomavirus 2 > Flashcards

10. Papillomavirus 2 Flashcards

1
Q

why does the virus prevent the keratinocytes from losing its nuclei?

A

normally, as keratinocytes differentiate they lose their nuclei

but the virus wants the cell to keep its nuclei so it stays in a pseudo S-phase with DNA replication machinery so the virus can replicate

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2
Q

describe the size and shape of the papillomavirus genome

A

8 kbp circular dsDNA

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3
Q

how many proteins does the genome encode for?

A

<10

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4
Q

what are the 3 functional regions of the genome?

A
  1. early genes
  2. late genes
  3. regulatory region (LCR or URR)
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5
Q

what do LCR and URR stand for?

A

LCR = long control region
URR = upstream regulatory region

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6
Q

what is the function of regulatory region (LCR and URR)? (3)

A
  1. transcription
  2. DNA replication (for E1 and E2)
  3. segregation of genome
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7
Q

are the 8 major proteins?

A
  1. E1
  2. E2
  3. E4
  4. E5
  5. E6
  6. E7
  7. L1
  8. L2
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8
Q

what is the only HPV enzyme and its function?

A

E1 –> DNA helicase

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9
Q

what are the 3 functions of E2?

A
  1. helicase loader
  2. transcriptional repressor
  3. segregation factor
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10
Q

what are the 3 overall roles of E1 and E2 in the replication cycle?

A
  1. viral DNA replication
  2. gene expression
  3. segregation
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11
Q

describe E2 acting as a transcriptional repressor

A

binds LCR and represses transcription of E6 and E7

required because if too much E6 and E7, things go wrong so E2 is a regulator, but then later in cancer cells E2 is not made so oncogenes can be made

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12
Q

what are the functions of E4 and E5 and their role in the replication cycle?

A

E4: disrupts cytokeratin network
E5: recycles growth factor receptors

have a role in genome amplification

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13
Q

what are the molecular functions of E6 and E7 and their role in the replication cycle?

A

E6: binds p53
E7: binds pRb

involved in viral oncogenes

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14
Q

what are the roles of L1 and L2?

A

L1 = major capsid protein
L2 = minor capsid protein

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15
Q

what causes senescence?

A

once a primary cell divides multiple times, its telomeres shorten at every division until the cell eventually dies

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16
Q

how does HPV prevent senescence?

A
  1. E6 activated telomerase to prevent telomere shortening
  2. E6/E7 inhibit p53/pRb
  3. cells become IMMORTALIZED
  4. Ras V12 oncogene activated
  5. cells become TRANSFORMED
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17
Q

what does it mean for cells to immortalized?

A

when cells express E6 and E7, they are not tumorigenic but can grow indefinitely

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18
Q

when do cells become tumorigenic? what does it mean for a cell to be tumorigenic?

A

when immortalized cells are transformed by adding mutations that activate Ras oncogene –> cells have additional growth properties and are tumorigenic

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19
Q

what 2 proteins maintain the viral genome as an episome?

A

E1 and E2

20
Q

what assay can be used to examine viral DNA? how is this helpful?

A

southern blot –> can visualize the presence of an episome, therefore the viral genome and functional and actively replicating

21
Q

what are organotypic raft cultures?

A

keratinocytes put at the interface btwn cell culture and air

22
Q

describe normal keratinocytes in raft cultures

A

epithelium is healthy, only basal layer is actively proliferating and synthesizing DNA

23
Q

describe HPV-immortalized keratinocytes in raft cultures

A

thicker epithelium, some differentiation
all cells maintain nuclei therefore all cells proliferating and making DNA replication machinery due to E6

24
Q

is cervical cancer rare or common?

A

rare relative to the high number of high-risk HPV infections

25
Q

do all high-risk HPV infections lead to cervical cancer?

A

no, but all cervical cancer is caused by high-risk HPV infection

26
Q

what is the difference between the viral genome during the normal viral life cycle vs cancers?

A

during the normal viral life cycle: the HPV genome is maintained as an episome

in cancers: the HPV genome is randomly integrated into the host chromosomes

27
Q

integration is a biomarker of:

A

integration is a biomarker of cancer progression

28
Q

how does viral genome integration allow for cancer progression?

A

E2 is disrupted –> E2 normally represses E6 and E7 transcription but now there can be higher expression of E6 and E7

29
Q

what happens when E2 is re-expressed in cervical carcinoma cells?

A

E6 and E7 are repressed so p53 and pRb are reactivated –> cells cannot proliferate and die by senescence/apoptosis

30
Q

why are cervical carcinoma cells “addicted” to oncogenes? what does this mean for cancer therapy?

A

any repression of E6 and E7 = death, so the cells require continuous expression of E6 and E7 for growth

this means E6 and E7 could be targets for cancer therapy

31
Q

what happens when E7 acts on pRB?

A

normally, pRB is in complex with E2F but E7 disrupts this complex –> allows E2F to stimulate proliferation (S phase)

32
Q

what does E2F do?

A

E2F is a family of transcription factors that regulate DNA replication machinery

33
Q

what is the result of E7-induced proliferation and how does E6 affect it?

A

E7-induced proliferation results in apoptosis

34
Q

how do cells normally progress into S phase?

A

normally, cyclin-Cdk2 phosphorylates pRb to release it from E2F so cell can undergo proliferation/S phase

35
Q

what are the 3 mechanisms by which E7 activates E2F?

A
  1. E7 binds pRb to induce its degradation by proteasome
  2. E7 binds and activates Cdk2
  3. E7 binds and inhibits p21 and p27 (natural inhibitors off cyclin/cdk2
36
Q

describe the protein structure of E7

A

small zinc-finger protein with LxCxE motif which binds Rb

37
Q

how does E6 inhibit p53? and 3 steps

A

E6 induces the degradation of p53 by the proteasome

  1. E6 forms complex with E6AP
  2. complex binds p53 and promotes its poly-ubiquitination
  3. poly-ubiquitinated p53 is targeted and degraded by proteasome
38
Q

what type of protein is E6AP?

A

cellular E3-ubiquitin ligase

39
Q

is E6AP normally involved in p53 degradation?

A

no!! the virus repurposed E6AP

40
Q

what happens if you express E6 in cells?

A

p53 levels immediately decrease

41
Q

describe the protein structure of E6

A

small protein with 2 zinc fingers

42
Q

describe the binding of E6 to E6AP

A

E6 binds to alpha helical LxxLL motif (hydrophobic amino acids) in E6AP

43
Q

telomerase is commonly expressed in what type of cells?

A

cancer cells

44
Q

describe the structure and components of telomerase

A

ribonucleoprotein complex

TER RNA and TERT protein

45
Q

what is the activity of TERT protein?

A

reverse transcriptase activity

46
Q

why does E6 activate telomerase? how?

A

to sustain cellular proliferation

E6 increases TERT transcription

MIMM 324 (37 decks)

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